Inheritance and selection of the mitochondrial genome

Newmeyer, D. D. & Ferguson-Miller, S. Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112, 481–490 https://doi.org/10.1016/s0092-8674(03)00116-8 (2003).

Starkov, A. A. The role of mitochondria in reactive oxygen species metabolism and signaling. Ann. N. Y. Acad. Sci. 1147, 37–52 https://doi.org/10.1196/annals.1427.015 (2008).

Garbincius, J. F. & Elrod, J. W. Mitochondrial calcium exchange in physiology and disease. Physiol. Rev. 102, 893–992 https://doi.org/10.1152/physrev.00041.2020 (2022).

Dolezal, P., Likic, V., Tachezy, J. & Lithgow, T. Evolution of the molecular machines for protein import into mitochondria. Science 313, 314–318 https://doi.org/10.1126/science.1127895 (2006).

Lightowlers, R. N., Taylor, R. W. & Turnbull, D. M. Mutations causing mitochondrial disease: what is new and what challenges remain. Science 349, 1494–1499 https://doi.org/10.1126/science.aac7516 (2015).

Sharma, P. & Sampath, H. Mitochondrial DNA integrity: role in health and disease. Cells 8, 100 https://doi.org/10.3390/cells8020100 (2019).

Schaefer, A. M., Taylor, R. W., Turnbull, D. M. & Chinnery, P. F. The epidemiology of mitochondrial disorders—past, present and future. Biochim. Biophys. Acta 1659, 115–120 https://doi.org/10.1016/j.bbabio.2004.09.005 (2004).

Klopstock, T. et al. Mitochondrial disorders. Dtsch. Ärztebl Int. 118, 741–748 https://doi.org/10.3238/arztebl.m2021.0251 (2021).

Ryzhkova, A. I. et al. Mitochondrial diseases caused by mtDNA mutations: a mini-review. Ther. Clin. Risk Manag. 14, 1933–1942 https://doi.org/10.2147/tcrm.S154863 (2018).

Wallace, D. C. Mitochondria as chi. Genetics 179, 727–735 https://doi.org/10.1534/genetics.104.91769 (2008).

Greiner, S., Sobanski, J. & Bock, R. Why are most organelle genomes transmitted maternally. BioEssays 37, 80–94 https://doi.org/10.1002/bies.201400110 (2015).

Stewart, J. B. & Larsson, N. G. Keeping mtDNA in shape between generations. PLoS Genet. 10, e1004670 https://doi.org/10.1371/journal.pgen.1004670 (2014).

Muller, H. J. The relation of recombination to mutational advance. Mutat. Res. 1, 2–9 https://doi.org/10.1016/0027-5107(64)90047-8 (1964).

Felsenstein, J. The evolutionary advantage of recombination. Genetics 78, 737–756 https://doi.org/10.1093/genetics/78.2.737 (1974).

Howe, D. K. & Denver, D. R. Muller’s Ratchet and compensatory mutation in Caenorhabditis briggsae mitochondrial genome evolution. BMC Evol. Biol. 8, 62 https://doi.org/10.1186/1471-2148-8-62 (2008).

Chao, L. Fitness of RNA virus decreased by Muller’s ratchet. Nature 348, 454–455 https://doi.org/10.1038/348454a0 (1990).

Andersson, D. I. & Hughes, D. Muller’s ratchet decreases fitness of a DNA-based microbe. Proc. Natl Acad. Sci. USA 93, 906–907 https://doi.org/10.1073/pnas.93.2.906 (1996).

Zeyl, C., Mizesko, M. & De Visser, J. A. G. M. Mutational meltdown in laboratory yeast population. Evolution 55, 909–917 https://doi.org/10.1111/j.0014-3820.2001.tb00608.x (2001).

Li, M. et al. Detecting heteroplasmy from high-throughput sequencing of complete human mitochondrial DNA genomes. Am. J. Hum. Genet. 87, 237–249 https://doi.org/10.1016/j.ajhg.2010.07.014 (2010).

Sosa, M. X. et al. Next-generation sequencing of human mitochondrial reference genomes uncovers high heteroplasmy frequency. PLoS Comput. Biol. 8, e1002737 https://doi.org/10.1371/journal.pcbi.1002737 (2012).

Payne, B. A. I. et al. Universal heteroplasmy of human mitochondrial DNA. Hum. Mol. Genet. 22, 384–390 https://doi.org/10.1093/hmg/dds435 (2013).

Gorman, G. S. et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann. Neurol. 77, 753–759 https://doi.org/10.1002/ana.24362 (2015).

Ng, Y. S. & Turnbull, D. M. Mitochondrial disease: genetics and management. J. Neurol. 263, 179–191 https://doi.org/10.1007/s00415-015-7884-3 (2016).

Cann, R. L., Brown, W. M. & Wilson, A. C. Polymorphic sites and the mechanism of evolution in human mitochondrial DNA. Genetics 106, 479–499 https://doi.org/10.1093/genetics/106.3.479 (1984).

Brown, G. G. & Simpson, M. V. Novel features of animal mtDNA evolution as shown by sequences of two rat cytochrome oxidase subunit II genes. Proc. Natl Acad. Sci. USA 79, 3246–3250 https://doi.org/10.1073/pnas.79.10.3246 (1982).

Hasegawa, M., Cao, Y. & Yang, Z. Preponderance of slightly deleterious polymorphism in mitochondrial DNA: nonsynonymous/synonymous rate ratio is much higher within species than between species. Mol. Biol. Evol. 15, 1499–1505 https://doi.org/10.1093/oxfordjournals.molbev.a025877 (1998).

Kivisild, T. et al. The role of selection in the evolution of human mitochondrial genomes. Genetics 172, 373–387 https://doi.org/10.1534/genetics.105.043901 (2006).

Moilanen, J. S. & Majamaa, K. Phylogenetic network and physicochemical properties of nonsynonymous mutations in the protein-coding genes of human mitochondrial DNA. Mol. Biol. Evol. 20, 1195–1210 https://doi.org/10.1093/molbev/msg121 (2003).

Ingman, M., Kaessmann, H., Pääbo, S. & Gyllensten, U. Mitochondrial genome variation and the origin of modern humans. Nature 408, 708–713 https://doi.org/10.1038/35047064 (2000).

Zhang, H. et al. Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission. Sci. Adv. 7, eabi5657 https://doi.org/10.1126/sciadv.abi5657 (2021).

Meshnik, L. et al. Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness. BMC Biol. 20, 40 https://doi.org/10.1186/s12915-022-01241-2 (2022).

Lieber, T., Jeedigunta, S. P., Palozzi, J. M., Lehmann, R. & Hurd, T. R. Mitochondrial fragmentation drives selective removal of deleterious mtDNA in the germline. Nature 570, 380–384 https://doi.org/10.1038/s41586-019-1213-4 (2019). This study identifies mitochondrial fragmentation as a prerequisite for the selective removal of deleterious mtDNA in the germline.

Chen, Z. et al. Mitochondrial DNA segregation and replication restrict the transmission of detrimental mutation. J. Cell Biol. 219, e201905160 https://doi.org/10.1083/jcb.201905160 (2020).

Chiang, A. C., McCartney, E., O’Farrell, P. H. & Ma, H. A genome-wide screen reveals that reducing mitochondrial DNA polymerase can promote elimination of deleterious mitochondrial mutations. Curr. Biol. 29, 4330–4336.e3 https://doi.org/10.1016/j.cub.2019.10.060 (2019).

Ma, H., Xu, H. & O’Farrell, P. H. Transmission of mitochondrial mutations and action of purifying selection in Drosophila melanogaster. Nat. Genet. 46, 393–397 https://doi.org/10.1038/ng.2919 (2014). This work resolves the timing and strength of purifying selection acting on deleterious mtDNA in the Drosophila germline.

Stewart, J. B. et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 6, e10 https://doi.org/10.1371/journal.pbio.0060010 (2008).

Sato, A. et al. Deletion-mutant mtDNA increases in somatic tissues but decreases in female germ cells with age. Genetics 177, 2031–2037 https://doi.org/10.1534/genetics.107.081026 (2007).

Fan, W. et al. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319, 958–962 https://doi.org/10.1126/science.1147786 (2008).

Li, M. et al. Transmission of human mtDNA heteroplasmy in the Genome of the Netherlands families: support for a variable-size bottleneck. Genome Res. 26, 417–426 https://doi.org/10.1101/gr.203216.115 (2016).

Zaidi, A. A. et al. Bottleneck and selection in the germline and maternal age influence transmission of mitochondrial DNA in human pedigrees. Proc. Natl Acad. Sci. USA 116, 25172–25178 https://doi.org/10.1073/pnas.1906331116 (2019). This human pedigree study disentangles the respective contributions of the bottleneck, selection and maternal age to mtDNA transmission.

Gupta, R. et al. Nuclear genetic control of mtDNA copy number and heteroplasmy in humans. Nature 620, 839–848 https://doi.org/10.1038/s41586-023-06426-5 (2023).

Wei, W. et al. Germline selection shapes human mitochondrial DNA diversity. Science 364, eaau6520 https://doi.org/10.1126/science.aau6520 (2019). This large-scale human study demonstrates that germline selection shapes the spectrum of transmitted mtDNA variants across the population.

Mok, B. Y. et al. CRISPR-free base editors with enhanced activity and expanded targeting scope in mitochondrial and nuclear DNA. Nat. Biotechnol. 40, 1378–1387 https://doi.org/10.1038/s41587-022-01256-8 (2022).

Stewart, J. B. & Chinnery, P. F. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat. Rev. Genet. 16, 530–542 https://doi.org/10.1038/nrg3966 (2015).

Yang, L. et al. Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD+ redox. Aging Cell 19, e13206 https://doi.org/10.1111/acel.13206 (2020).

Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 https://doi.org/10.1038/nature02517 (2004).

Ryall, C., Chinnery, P. F. & van den Ameele, J. Common principles underlie mitochondrial DNA heteroplasmy dynamics in the germline and soma. Annu. Rev. Genom. Hum. Genet. 27, 247–275 https://doi.org/10.1146/annurev-genom-120324-032239 (2026).

Árnadóttir, E. R. et al. The rate and nature of mitochondrial DNA mutations in human pedigrees. Cell 187, 3904–3918.e8 https://doi.org/10.1016/j.cell.2024.05.022 (2024).

Brown, W. M., George, M. Jr & Wilson, A. C. Rapid evolution of animal mitochondrial DNA. Proc. Natl Acad. Sci. USA 76, 1967–1971 https://doi.org/10.1073/pnas.76.4.1967 (1979).

Arbeithuber, B. et al. Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues. PLoS Biol. 18, e3000745 https://doi.org/10.1371/journal.pbio.3000745 (2020).

Hauswirth, W. W. & Laipis, P. J. Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows. Proc. Natl Acad. Sci. USA 79, 4686–4690 https://doi.org/10.1073/pnas.79.15.4686 (1982).

Jenuth, J. P., Peterson, A. C., Fu, K. & Shoubridge, E. A. Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nat. Genet. 14, 146–151 https://doi.org/10.1038/ng1096-146 (1996).

Cree, L. M. et al. A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat. Genet. 40, 249–254 https://doi.org/10.1038/ng.2007.63 (2008).

Brown, D. T., Samuels, D. C., Michael, E. M., Turnbull, D. M. & Chinnery, P. F. Random genetic drift determines the level of mutant mtDNA in human primary oocytes. Am. J. Hum. Genet. 68, 533–536 https://doi.org/10.1086/318190 (2001).

Floros, V. I. et al. Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos. Nat. Cell Biol. 20, 144–151 https://doi.org/10.1038/s41556-017-0017-8 (2018). This study characterizes the developmental genetic bottleneck directly in human embryos, extending the model beyond animal systems.

Iwata, H. et al. Effect of maternal age on mitochondrial DNA copy number, ATP content and IVF outcome of bovine oocytes. Reprod. Fertil. Dev. 23, 424–432 https://doi.org/10.1071/rd10133 (2011).

Otten, A. B. C. et al. Differences in strength and timing of the mtDNA bottleneck between zebrafish germline and non-germline cells. Cell Rep. 16, 622–630 https://doi.org/10.1016/j.celrep.2016.06.023 (2016).

Clark, K. A. et al. Selfish little circles: transmission bias and evolution of large deletion-bearing mitochondrial DNA in Caenorhabditis briggsae nematodes. PLoS One 7, e41433 https://doi.org/10.1371/journal.pone.0041433 (2012).

Dubie, J. J., Caraway, A. R., Stout, M. M., Katju, V. & Bergthorsson, U. The conflict within: origin, proliferation and persistence of a spontaneously arising selfish mitochondrial genome. Philos. Trans. R. Soc. B 375, 20190174 https://doi.org/10.1098/rstb.2019.0174 (2020).

Hill, J. H., Chen, Z. & Xu, H. Selective propagation of functional mitochondrial DNA during oogenesis restricts the transmission of a deleterious mitochondrial variant. Nat. Genet. 46, 389–392 https://doi.org/10.1038/ng.2920 (2014). This study shows that selective propagation of functional mtDNA during oogenesis restricts transmission of a deleterious variant.

Ru, Y. et al. Maternal age enhances purifying selection on pathogenic mutations in complex I genes of mammalian mtDNA. Nat. Aging 4, 1211–1230 https://doi.org/10.1038/s43587-024-00672-6 (2024). This study shows that advancing maternal age intensifies purifying selection against pathogenic complex I mtDNA mutations.

Xie, Q. et al. Trans-generational maintenance of mitochondrial DNA integrity in oocytes during early folliculogenesis. PLoS Genet. 21, e1011562 https://doi.org/10.1371/journal.pgen.1011562 (2025). This study demonstrates that mtDNA integrity is maintained across generations within oocytes during early folliculogenesis.

Wei, W. & Chinnery, P. F. Inheritance of mitochondrial DNA in humans: implications for rare and common diseases. J. Intern. Med. 287, 634–644 https://doi.org/10.1111/joim.13047 (2020).

Freyer, C. et al. Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. Nat. Genet. 44, 1282–1285 https://doi.org/10.1038/ng.2427 (2012).

Frison, M. et al. Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations. Science 390, 156–163 https://doi.org/10.1126/science.adr5438 (2025). This study establishes ubiquitin-mediated mitophagy as a regulator of which mtDNA mutations are inherited.

Latorre-Pellicer, A. et al. Regulation of mother-to-offspring transmission of mtDNA heteroplasmy. Cell Metab. 30, 1120–1130.e5 https://doi.org/10.1016/j.cmet.2019.09.007 (2019).

Schwartz, A. Z. A., Tsyba, N., Abdu, Y., Patel, M. R. & Nance, J. Independent regulation of mitochondrial DNA quantity and quality in Caenorhabditis elegans primordial germ cells. eLife 11, e80396 https://doi.org/10.7554/eLife.80396 (2022).

Zhang, C., Chen, Z., Ma, H. & Xu, H. Replication competition drives the selective mtDNA inheritance in Drosophila ovary. Cell Rep. 44, 116221 https://doi.org/10.1016/j.celrep.2025.116221.

Finsterer J. Obstetric involvement in mitochondrial disorders: a review. Medicine 102, e33336 https://doi.org/10.1097/md.0000000000033336 (2023).

de Laat, P., Fleuren, L. H. J., Bekker, M. N., Smeitink, J. A. M. & Janssen, M. C. H. Obstetric complications in carriers of the m.3243A>G mutation, a retrospective cohort study on maternal and fetal outcome. Mitochondrion 25, 98–103 https://doi.org/10.1016/j.mito.2015.10.005 (2015).

Kuleva, M. et al. Increased incidence of obstetric complications in women carrying mitochondrial DNA mutations: a retrospective cohort study in a single tertiary centre. BJOG 126, 1372–1379 https://doi.org/10.1111/1471-0528.15515 (2019).

Chandra, S. R., Issac, T. G., Gayathri, N., Gupta, N. & Abbas, M. M. A typical case of myoclonic epilepsy with ragged red fibers (MERRF) and the lessons learned. J. Postgrad. Med. 61, 200–202 https://doi.org/10.4103/0022-3859.150905 (2015).

Pallotti, F. et al. A wide range of 3243A>G/tRNALeu(UUR) (MELAS) mutation loads may segregate in offspring through the female germline bottleneck. PLoS ONE 9, e96663 https://doi.org/10.1371/journal.pone.0096663 (2014).

Ji, L. et al. Deep sequencing shows that accumulation of potentially pathogenic mtDNA mutations rather than mtDNA copy numbers may be associated with early embryonic loss. J. Assist. Reprod. Genet. 37, 2181–2188 https://doi.org/10.1007/s10815-020-01893-5 (2020).

Feeney, C. L. et al. A case-comparison study of pregnant women with mitochondrial disease – what to expect? BJOG 126, 1380–1389 https://doi.org/10.1111/1471-0528.15667 (2019).

Sanchez-Lechuga, B. et al. A retrospective cohort study evaluating pregnancy outcomes in women with MIDD. Acta Diabetol. 61, 323–331 https://doi.org/10.1007/s00592-023-02202-z (2024).

Kuikka, P., Nikkinen, H., Majamaa, K. & Martikainen, M. H. Obstetric history of women with m.3243A>G: an observational cohort study. J. Med. Genet. 63, 201–204 https://doi.org/10.1136/jmg-2025-110875 (2026).

Glass, H. C. et al. Outcomes for extremely premature infants. Anesth. Analg. 120, 1337–1351 https://doi.org/10.1213/ane.0000000000000705 (2015).

Han, L. et al. Increased mtDNA mutation frequency in oocytes causes epigenetic alterations and embryonic defects. Natl Sci. Rev. 9, nwac136 https://doi.org/10.1093/nsr/nwac136 (2022).

Burr, S. P. et al. Cell lineage-specific mitochondrial resilience during mammalian organogenesis. Cell 186, 1212–1229.e21 https://doi.org/10.1016/j.cell.2023.01.034 (2023).

Ma, H. et al. Deleterious mtDNA mutations are common in mature oocytes. Biol. Reprod. 102, 607–619 https://doi.org/10.1093/biolre/ioz202 (2020).

Kaipia, A. & Hsueh, A. J. W. Regulation of ovarian follicle atresia. Annu. Rev. Physiol. 59, 349–363 https://doi.org/10.1146/annurev.physiol.59.1.349 (1997).

Macklon, N. S. & Fauser, B. C. J. M. Follicle development during the normal menstrual cycle. Maturitas 30, 181–188 https://doi.org/10.1016/S0378-5122(98)00072-3 (1998).

Krakauer, D. C. & Mira, A. Mitochondria and germ-cell death. Nature 400, 125–126 https://doi.org/10.1038/22026 (1999).

Xie, Q. et al. Secondary follicles enable efficient germline mtDNA base editing at hard-to-edit site. Mol. Ther. Nucleic Acids 35, 102170 https://doi.org/10.1016/j.omtn.2024.102170 (2024).

Flowers, S. et al. Regulation of defective mitochondrial DNA accumulation and transmission in C. elegans by the programmed cell death and aging pathways. eLife 12, e79725 https://doi.org/10.7554/eLife.79725 (2023).

Pikó, L. & Taylor, K. D. Amounts of mitochondrial DNA and abundance of some mitochondrial gene transcripts in early mouse embryos. Dev. Biol. 123, 364–374 https://doi.org/10.1016/0012-1606(87)90395-2 (1987).

Wolf, D. P., Hayama, T. & Mitalipov, S. Mitochondrial genome inheritance and replacement in the human germline. EMBO J. 36, 2177–2181 https://doi.org/10.15252/embj.201797606 (2017).

St. John, J. C., Facucho-Oliveira, J., Jiang, Y., Kelly, R. & Salah, R. Mitochondrial DNA transmission, replication and inheritance: a journey from the gamete through the embryo and into offspring and embryonic stem cells. Hum. Reprod. Update 16, 488–509 https://doi.org/10.1093/humupd/dmq002 (2010).

Ijuin, A. et al. Mitochondrial DNA mutations can influence the post-implantation development of human mosaic embryos. Front. Cell Dev. Biol. 11, 1215626 https://doi.org/10.3389/fcell.2023.1215626 (2023).

Lima, A. et al. Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development. Nat. Metab. 3, 1091–1108 https://doi.org/10.1038/s42255-021-00422-7 (2021).

Narendra, D. P. & Youle, R. J. The role of PINK1–Parkin in mitochondrial quality control. Nat. Cell Biol. 26, 1639–1651 https://doi.org/10.1038/s41556-024-01513-9 (2024).

Baracca, A. et al. Biochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993. Biochim. Biophys. Acta 1767, 913–919 https://doi.org/10.1016/j.bbabio.2007.05.005 (2007).

Sgarbi, G. et al. Inefficient coupling between proton transport and ATP synthesis may be the pathogenic mechanism for NARP and Leigh syndrome resulting from the T8993G mutation in mtDNA. Biochem. J. 395, 493–500 https://doi.org/10.1042/bj20051748 (2006).

Chen, Y. et al. AMPK suppression due to obesity drives oocyte mtDNA heteroplasmy via ATF5-POLG axis. Adv. Sci. 11, e2307480 https://doi.org/10.1002/advs.202307480 (2024).

Zorov, D. B., Juhaszova, M. & Sollott, S. J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 94, 909–950 https://doi.org/10.1152/physrev.00026.2013 (2014).

Kataura, T. et al. NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy. EMBO J. 42, e111372 https://doi.org/10.15252/embj.2022111372 (2023).

Long, S. et al. Maintaining mitochondrial DNA copy number mitigates ROS-induced oocyte decline and female reproductive aging. Commun. Biol. 7, 1229 https://doi.org/10.1038/s42003-024-06888-x (2024).

Hayashi, Y. et al. Distinct requirements for energy metabolism in mouse primordial germ cells and their reprogramming to embryonic germ cells. Proc. Natl Acad. Sci. USA 114, 8289–8294 https://doi.org/10.1073/pnas.1620915114 (2017).

Wang, Z. H. et al. Mechanical stimulation from the surrounding tissue activates mitochondrial energy metabolism in Drosophila differentiating germ cells. Dev. Cell 58, 2249–2260.e9 https://doi.org/10.1016/j.devcel.2023.08.007 (2023).

Zhang, Y. et al. PINK1 inhibits local protein synthesis to limit transmission of deleterious mitochondrial DNA mutations. Mol. Cell 73, 1127–1137.e5 https://doi.org/10.1016/j.molcel.2019.01.013 (2019). This study shows that PINK1 restricts transmission of deleterious mtDNA mutations by inhibiting local mitochondrial protein synthesis.

Palozzi, J. M. et al. Mitochondrial DNA quality control in the female germline requires a unique programmed mitophagy. Cell Metab. 34, 1809–1823.e6 https://doi.org/10.1016/j.cmet.2022.10.005 (2022). This work defines a germline-specific programmed mitophagy pathway that enforces mtDNA quality control in oocytes.

Kremer, L. S. et al. The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy. Sci. Adv. 11, eaea4660 https://doi.org/10.1126/sciadv.aea4660 (2025). This study implicates BCL2L13-mediated autophagy in germline purifying selection against mutant mtDNA.

Gitschlag, B. L. et al. Homeostatic responses regulate selfish mitochondrial genome dynamics in C. elegans. Cell Metab. 24, 91–103 https://doi.org/10.1016/j.cmet.2016.06.008 (2016). This study reveals a programmed mitophagy at the oocyte-to-zygote transition that promotes mitochondrial lineage endurance.

Valenci, I., Yonai, L., Bar-Yaacov, D., Mishmar, D. & Ben-Zvi, A. Parkin modulates heteroplasmy of truncated mtDNA in Caenorhabditis elegans. Mitochondrion 20, 64–70 https://doi.org/10.1016/j.mito.2014.11.001 (2015).

Kremer, L. S. et al. A role for BCL2L13 and autophagy in germline purifying selection of mtDNA. PLoS Genet. 19, e1010573 https://doi.org/10.1371/journal.pgen.1010573 (2023).

Thendral, S. B. et al. Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance. Nat. Cell Biol. 28, 268–284 https://doi.org/10.1038/s41556-025-01854-z (2026).

Boudoures, A. L. et al. Obesity-exposed oocytes accumulate and transmit damaged mitochondria due to an inability to activate mitophagy. Dev. Biol. 426, 126–138 https://doi.org/10.1016/j.ydbio.2017.04.005 (2017).

Tsukamoto, S. et al. Autophagy is essential for preimplantation development of mouse embryos. Science 321, 117–120 https://doi.org/10.1126/science.1154822 (2008).

Rojansky, R., Cha, M. Y. & Chan, D. C. Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. eLife 5, e17896 https://doi.org/10.7554/eLife.17896 (2016).

Wiesner, R. J., Rüegg, J. C. & Morano, I. Counting target molecules by exponential polymerase chain reaction: copy number of mitochondrial DNA in rat tissues. Biochem. Biophys. Res. Commun. 183, 553–559 https://doi.org/10.1016/0006-291x(92)90517-o (1992).

Cox, R. T. & Spradling, A. C. A Balbiani body and the fusome mediate mitochondrial inheritance during Drosophila oogenesis. Development 130, 1579–1590 https://doi.org/10.1242/dev.00365 (2003).

Chiaratti, M. R. Uncovering the important role of mitochondrial dynamics in oogenesis: impact on fertility and metabolic disorder transmission. Biophys. Rev. 13, 967–981 https://doi.org/10.1007/s12551-021-00891-w (2021).

Udagawa, O. et al. Mitochondrial fission factor Drp1 maintains oocyte quality via dynamic rearrangement of multiple organelles. Curr. Biol. 24, 2451–2458 https://doi.org/10.1016/j.cub.2014.08.060 (2014).

Pikó, L. & Matsumoto, L. Number of mitochondria and some properties of mitochondrial DNA in the mouse egg. Dev. Biol. 49, 1–10 https://doi.org/10.1016/0012-1606(76)90253-0 (1976).

Michaels, G. S., Hauswirth, W. W. & Laipis, P. J. Mitochondrial DNA copy number in bovine oocytes and somatic cells. Dev. Biol. 94, 246–251 https://doi.org/10.1016/0012-1606(82)90088-4 (1982).

Moraes, C. T., Kenyon, L. & Hao, H. Mechanisms of human mitochondrial DNA maintenance: the determining role of primary sequence and length over function. Mol. Biol. Cell 10, 3345–3356 https://doi.org/10.1091/mbc.10.10.3345 (1999).

Diaz, F. et al. Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control. Nucleic Acids Res. 30, 4626–4633 https://doi.org/10.1093/nar/gkf602 (2002).

Rand, D. M. Population genetics of the cytoplasm and the units of selection on mitochondrial DNA in Drosophila melanogaster. Genetica 139, 685–697 https://doi.org/10.1007/s10709-011-9576-y (2011).

Ma, H. & O’Farrell, P. H. Selfish drive can trump function when animal mitochondrial genomes compete. Nat. Genet. 48, 798–802 https://doi.org/10.1038/ng.3587 (2016).

Kang, E. et al. Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature 540, 270–275 https://doi.org/10.1038/nature20592 (2016).

Yamada, M. et al. Genetic drift can compromise mitochondrial replacement by nuclear transfer in human oocytes. Cell Stem Cell 18, 749–754 https://doi.org/10.1016/j.stem.2016.04.001 (2016).

Hyslop, L. A. et al. Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature 534, 383–386 https://doi.org/10.1038/nature18303 (2016).

Ameur, A. et al. Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet. 7, e1002028 https://doi.org/10.1371/journal.pgen.1002028 (2011).

Itsara, L. S. et al. Oxidative stress is not a major contributor to somatic mitochondrial DNA mutations. PLoS Genet. 10, e1003974 https://doi.org/10.1371/journal.pgen.1003974 (2014).

Kennedy, S. R., Salk, J. J., Schmitt, M. W. & Loeb, L. A. Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet. 9, e1003794 https://doi.org/10.1371/journal.pgen.1003794 (2013).

Khrapko, K. et al. Mitochondrial mutational spectra in human cells and tissues. Proc. Natl Acad. Sci. USA 94, 13798–13803 https://doi.org/10.1073/pnas.94.25.13798 (1997).

Zheng, W., Khrapko, K., Coller, H. A., Thilly, W. G. & Copeland, W. C. Origins of human mitochondrial point mutations as DNA polymerase gamma-mediated errors. Mutat. Res. 599, 11–20 https://doi.org/10.1016/j.mrfmmm.2005.12.012 (2006).

Arbeithuber, B. et al. Allele frequency selection and no age-related increase in human oocyte mitochondrial mutations. Sci. Adv. 11, eadw4954 https://doi.org/10.1126/sciadv.adw4954 (2025).

Arbeithuber, B. et al. Advanced age increases frequencies of de novo mitochondrial mutations in macaque oocytes and somatic tissues. Proc. Natl Acad. Sci. USA 119, e2118740119 https://doi.org/10.1073/pnas.2118740119 (2022).

Sun, N., Youle, R. J. & Finkel, T. The mitochondrial basis of aging. Mol. Cell 61, 654–666 https://doi.org/10.1016/j.molcel.2016.01.028 (2016).

Pinto, M. & Moraes, C. T. Mechanisms linking mtDNA damage and aging. Free Radic. Biol. Med. 85, 250–258 https://doi.org/10.1016/j.freeradbiomed.2015.05.005 (2015).

Bratic, A. & Larsson, N. G. The role of mitochondria in aging. J. Clin. Investig. 123, 951–957 https://doi.org/10.1172/jci64125 (2013).

Chocron, E. S., Munkácsy, E. & Pickering, A. M. Cause or casualty: The role of mitochondrial DNA in aging and age-associated disease. Biochim. Biophys. Acta Mol. Basis Dis. 1865, 285–297 https://doi.org/10.1016/j.bbadis.2018.09.035 (2019).

Rebolledo-Jaramillo, B. et al. Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proc. Natl Acad. Sci. USA 111, 15474–15479 https://doi.org/10.1073/pnas.1409328111 (2014). This human study defines the maternal-age effect superimposed on a severe germline bottleneck during mtDNA inheritance.

Barritt, J. A., Cohen, J. & Brenner, C. A. Mitochondrial DNA point mutation in human oocytes is associated with maternal age. Reprod. BioMed. Online 1, 96–100 https://doi.org/10.1016/S1472-6483(10)61946-3 (2000).

Sagan, L. On the origin of mitosing cells. J. Theor. Biol. 14, 255–274 https://doi.org/10.1016/0022-5193(67)90079-3 (1967).

Schwartz, R. M. & Dayhoff, M. O. Origins of prokaryotes, eukaryotes, mitochondria, and chloroplasts. Science 199, 395–403 https://doi.org/10.1126/science.202030 (1978).

Bonen, L., Cunningham, R. S., Gray, M. W. & Doolittle, W. F. Wheat embryo mitochondrial 18S ribosomal RNA: evidence for its prokaryotic nature. Nucleic Acids Res. 4, 663–671 https://doi.org/10.1093/nar/4.3.663 (1977).

Roger, A. J., Muñoz-Gómez, S. A. & Kamikawa, R. The origin and diversification of mitochondria. Curr. Biol. 27, R1177–R1192 https://doi.org/10.1016/j.cub.2017.09.015 (2017).

Martijn, J., Vosseberg, J., Guy, L., Offre, P. & Ettema, T. J. G. Deep mitochondrial origin outside the sampled alphaproteobacteria. Nature 557, 101–105 https://doi.org/10.1038/s41586-018-0059-5 (2018).

Muñoz-Gómez, S. A. et al. Site-and-branch-heterogeneous analyses of an expanded dataset favour mitochondria as sister to known Alphaproteobacteria. Nat. Ecol. Evol. 6, 253–262 https://doi.org/10.1038/s41559-021-01638-2 (2022).

Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 https://doi.org/10.1038/290457a0 (1981).

Silva-Pinheiro, P. & Minczuk, M. The potential of mitochondrial genome engineering. Nat. Rev. Genet. 23, 199–214 https://doi.org/10.1038/s41576-021-00432-x (2022).

Gustafsson, C. M., Falkenberg, M. & Larsson, N. G. Maintenance and expression of mammalian mitochondrial DNA. Annu. Rev. Biochem. 85, 133–160 https://doi.org/10.1146/annurev-biochem-060815-014402 (2016).

Shoubridge, E. A. & Wai, T. Mitochondrial DNA and the mammalian oocyte. Curr. Top. Dev. Biol. 77, 87–111 https://doi.org/10.1016/s0070-2153(06)77004-1 (2007).

D’Erchia, A. M. et al. Tissue-specific mtDNA abundance from exome data and its correlation with mitochondrial transcription, mass and respiratory activity. Mitochondrion 20, 13–21 https://doi.org/10.1016/j.mito.2014.10.005 (2015).

Song, G. J. & Lewis, V. Mitochondrial DNA integrity and copy number in sperm from infertile men. Fertil. Steril. 90, 2238–2244 https://doi.org/10.1016/j.fertnstert.2007.10.059 (2008).

Bogenhagen, D. & Clayton, D. A. Mouse L cell mitochondrial DNA molecules are selected randomly for replication throughout the cell cycle. Cell 11, 719–727 https://doi.org/10.1016/0092-8674(77)90286-0 (1977).

Robberson, D. L. & Clayton, D. A. Replication of mitochondrial DNA in mouse L cells and their thymidine kinase–derivatives: displacement replication on a covalently-closed circular template. Proc. Natl Acad. Sci. USA 69, 3810–3814 https://doi.org/10.1073/pnas.69.12.3810 (1972).

Gillum, A. M. & Clayton, D. A. Mechanism of mitochondrial DNA replication in mouse L-cells: RNA priming during the initiation of heavy-strand synthesis. J. Mol. Biol. 135, 353–368 https://doi.org/10.1016/0022-2836(79)90441-8 (1979).

Fusté, J. M. et al. Mitochondrial RNA polymerase is needed for activation of the origin of light-strand DNA replication. Mol. Cell 37, 67–78 https://doi.org/10.1016/j.molcel.2009.12.021 (2010).

Lynch, M. The lower bound to the evolution of mutation rates. Genome Biol. Evol. 3, 1107–1118 https://doi.org/10.1093/gbe/evr066 (2011).

Graziewicz, M. A., Longley, M. J. & Copeland, W. C. DNA polymerase γ in mitochondrial DNA replication and repair. Chem. Rev. 106, 383–405 https://doi.org/10.1021/cr040463d (2006).

Stewart, J. B. & Chinnery, P. F. Extreme heterogeneity of human mitochondrial DNA from organelles to populations. Nat. Rev. Genet. 22, 106–118 https://doi.org/10.1038/s41576-020-00284-x (2021).

Kazak, L., Reyes, A. & Holt, I. J. Minimizing the damage: repair pathways keep mitochondrial DNA intact. Nat. Rev. Mol. Cell Biol. 13, 659–671 https://doi.org/10.1038/nrm3439 (2012).

Farge, G. & Falkenberg, M. Organization of DNA in mammalian mitochondria. Int. J. Mol. Sci. 20, 2770 https://doi.org/10.3390/ijms20112770 (2019).

Qian, W. et al. Chemoptogenetic damage to mitochondria causes rapid telomere dysfunction. Proc. Natl Acad. Sci. USA 116, 18435–18444 https://doi.org/10.1073/pnas.1910574116 (2019).

Romesberg, A. & Van Houten, B. Targeting mitochondrial function with chemoptogenetics. Biomedicines 10, 2459 https://doi.org/10.3390/biomedicines10102459 (2022).

Yakes, F. M. & Van Houten, B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc. Natl Acad. Sci. USA 94, 514–519 https://doi.org/10.1073/pnas.94.2.514 (1997).

Lott, M. T. et al. mtDNA variation and analysis using Mitomap and Mitomaster. Curr. Protoc. Bioinform. 44, 1.23.1–1.23.26 https://doi.org/10.1002/0471250953.bi0123s44 (2013).

Holt, I. J., Harding, A. E. & Morgan-Hughes, J. A. Deletions of muscle mitochondrial DNA in mitochondrial myopathies: sequence analysis and possible mechanisms. Nucleic Acids Res. 17, 4465–4469 https://doi.org/10.1093/nar/17.12.4465 (1989).

Gorman, G. S. et al. Mitochondrial diseases. Nat. Rev. Dis. Primers 2, 16080 https://doi.org/10.1038/nrdp.2016.80 (2016).

Tatuch, Y. et al. Heteroplasmic mtDNA mutation (T→G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am. J. Hum. Genet. 50, 852–858 (1992).

Elson, J. L., Samuels, D. C., Turnbull, D. M. & Chinnery, P. F. Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. Am. J. Hum. Genet. 68, 802–806 https://doi.org/10.1086/318801 (2001).

Chinnery, P. F. & Samuels, D. C. Relaxed replication of mtDNA: a model with implications for the expression of disease. Am. J. Hum. Genet. 64, 1158–1165 https://doi.org/10.1086/302311 (1999).

Yu-Wai-Man, P. & Chinnery, P. F. Leber hereditary optic neuropathy. In GeneReviews (eds Adam, M. P. et al.) https://www.ncbi.nlm.nih.gov/sites/books/NBK1174/ (Univ. of Washington, 2000).

Luo, S. et al. Biparental inheritance of mitochondrial DNA in humans. Proc. Natl Acad. Sci. USA 115, 13039–13044 https://doi.org/10.1073/pnas.1810946115 (2018).

Schwartz, M. & Vissing, J. Paternal inheritance of mitochondrial DNA. N. Engl. J. Med. 347, 576–580 https://doi.org/10.1056/NEJMoa020350 (2002).

Wei, W. et al. Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans. Nat. Commun. 11, 1740 https://doi.org/10.1038/s41467-020-15336-3 (2020).

Rius, R. et al. Biparental inheritance of mitochondrial DNA in humans is not a common phenomenon. Genet. Med. 21, 2823–2826 https://doi.org/10.1038/s41436-019-0568-0 (2019).

Lutz-Bonengel, S. et al. Evidence for multi-copy Mega-NUMTs in the human genome. Nucleic Acids Res. 49, 1517–1531 https://doi.org/10.1093/nar/gkaa1271 (2021).

Bai, R. et al. Interference of nuclear mitochondrial DNA segments in mitochondrial DNA testing resembles biparental transmission of mitochondrial DNA in humans. Genet. Med. 23, 1514–1521 https://doi.org/10.1038/s41436-021-01166-1 (2021).

Sato, M. & Sato, K. Maternal inheritance of mitochondrial DNA by diverse mechanisms to eliminate paternal mitochondrial DNA. Biochim. Biophys. Acta Mol. Cell Res. 1833, 1979–1984 https://doi.org/10.1016/j.bbamcr.2013.03.010 (2013).

Lee, W. et al. Molecular basis for maternal inheritance of human mitochondrial DNA. Nat. Genet. 55, 1632–1639 https://doi.org/10.1038/s41588-023-01505-9 (2023).

Yu, Z., O’Farrell, P. H., Yakubovich, N. & DeLuca, S. Z. The mitochondrial DNA polymerase promotes elimination of paternal mitochondrial genomes. Curr. Biol. 27, 1033–1039 https://doi.org/10.1016/j.cub.2017.02.014 (2017).

Sato, M. & Sato, K. Degradation of paternal mitochondria by fertilization-triggered autophagy in C. elegans embryos. Science 334, 1141–1144 https://doi.org/10.1126/science.1210333 (2011).

Sharpley, M. S. et al. Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition. Cell 151, 333–343 https://doi.org/10.1016/j.cell.2012.09.004 (2012).

Havird, J. C. et al. Selfish mitonuclear conflict. Curr. Biol. 29, R496–R511 https://doi.org/10.1016/j.cub.2019.03.020 (2019).

Barton, L. J. & Lin, B. Harnessing the power of Drosophila primordial germ cell migration. Cold Spring Harb. Perspect. Biol. 18, a041800 https://doi.org/10.1101/cshperspect.a041800 (2026).

O’Neill, K. E. et al. Anatomic nomenclature and 3-dimensional regional model of the human ovary: call for a new paradigm. Am. J. Obstet. Gynecol. 228, 270–275.e4 https://doi.org/10.1016/j.ajog.2022.09.040 (2023).

Huynh, J.-R. & St Johnston, D. The origin of asymmetry: early polarisation of the Drosophila germline cyst and oocyte. Curr. Biol. 14, R438–R449 https://doi.org/10.1016/j.cub.2004.05.040 (2004).

Wear, H. M., McPike, M. J. & Watanabe, K. H. From primordial germ cells to primordial follicles: a review and visual representation of early ovarian development in mice. J. Ovarian Res. 9, 36 https://doi.org/10.1186/s13048-016-0246-7 (2016).